Over the past five years, the applicant has developed a research and mentoring program that is central to clinical drug abuse research at UCLA. He is P.I. on a training grant (T32 MH19200), which supports 2 predoctoral students and 3 postdoctoral trainees. He has also developed a clinical research education program (R25 DA14593) to provide additional training in clinical research for clinically trained physicians or psychologists. These training programs complement two other institutional training grants on which he participates, the Psychobiology Training Program, T32 MH017140 (Dr. Andrew Leuchter, P.I.), and the Drug Abuse Training Program, T32 DA007272 (Dr. Richard Rawson, P.I.). These programs specifically complement the mentoring component of the proposed Midcareer Investigator Award in Patient-oriented Research. The applicant's research program has emphasized study of neurobiological changes associated with methamphetamine dependence. In addition, he has developed a human laboratory program that uses information regarding these neurobiological changes in order to inform the development of medication treatments for stimulant dependence. He proposes to expand this research program to include studies of neuroimmune effects of stress in order to characterize factors important in stimulant dependence more fully. "Stress" is hypothesized to contribute to relapse in individuals with substance dependence and this has been studied using preclinical animal models, exemplified by the reinstatement model of relapse. In the reinstatement model, extinguished drug-seeking behavior is reinstated by exposure to a stressor or by administration of a "priming" dose of the previously self-administered drug. The applicant proposes to examine the effects of exposure to an experimental stressor and of administration of a priming dose of methamphetamine on neuroimmune measures, drug craving, and on drug seeking behavior in methamphetamine dependent volunteers. The role played by changes in neuroimmune measures following exposure to stress or methamphetamine in mediating the development of craving and drug-seeking behavior will then be examined. A more complete understanding of stress-related aspects of addiction will facilitate the development of treatments for stimulant dependence.